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ACIP Grading of Recommendations Assessment, Development and Evaluation (GRADE) for Hepatitis B (HepB) Vaccine in Adults						Print
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										Introduction
Since hepatitis B (HepB) vaccine introduction in 1982, there have been substantial declines in reported hepatitis B cases. However, despite reductions in hepatitis B incidence achieved through incremental HepB vaccine policy over the past four decades, from a high of 26,654 reported cases (287,000 estimated) in 1985 to a low of 2,791 reported cases (19,200 estimated) in 2014, progress has stalled in further reducing hepatitis B incidence (1). In 2018, the reported HepB vaccination coverage (≥3 doses) was overall 30.0% for adults ≥19 years old, demonstrating small increases in coverage throughout the past four decades (2), including low coverage among persons in risk groups recommended for vaccination (e.g., 33% coverage among persons with chronic liver disease).
As part of ACIP’s process, a systematic review and Grading of Recommendations Assessment, Development and Evaluation (GRADE) of the evidence of benefits and harms was conducted and presented to ACIP. The GRADE approach for evaluating evidence, which indicates the certainty of estimates from the available body of evidence, was adopted by ACIP in 2010 (3).
Methods
During September 2019–October 2021, the ACIP Hepatitis Work Group held monthly conference calls to review and discuss scientific evidence relevant to the use of HepB vaccines in a universal adult vaccination recommendation. The Work Group identified critical and important outcomes for inclusion in the GRADE tables, conducted a systematic review of the evidence, and subsequently reviewed and discussed findings and evidence quality (www.cdc.gov/vaccines/acip/recs/index.html) (3) (Table 1). In the GRADE approach, evidence certainty can range from type 1 (high certainty) to type 4 (very low certainty). Evidence was found to be available only for the cardiovascular and serious adverse events outcomes. Ultimately, no studies were available comparing the two strategies of universal and risk-based adult HepB vaccination. Thus, only the outcomes of serious adverse events and cardiovascular events associated with Heplisav-B were assessed, as noted below.
2019 Viral Hepatitis Surveillance Report. 2021, Centers for Disease Control and Prevention.
Lu, P.J., et al., Surveillance of Vaccination Coverage Among Adult Populations -United States, 2018. MMWR Surveill Summ, 2021. 70(3): p. 1-26.
CDC. New Framework (GRADE) for Development of Evidence-Based Recommendations by the Advisory Committee on Immunization Practices. *MMWR* Recomm Rep 2012;61:327.Table 1: Policy Question and PICO
Table 1: Policy Question and PICO
Policy question:
Should all hepatitis B (HepB)-unvaccinated adults receive HepB vaccination?Population
Previously unvaccinated adults age ≥ 18 yearsIntervention
Universal vaccination strategy (2- and 3-dose schedules)Comparison
Current risk-based vaccination strategy (2- and 3-dose schedules)Outcomes
Incidence of hepatitis B
Morbidity related to hepatitis B
Mortality related to hepatitis B
Serious adverse events associated with the 2-dose vaccine** This outcome is solely aimed at assessing the 2-dose Heplisav-B vaccine (approved in 2017). The 3-dose HepB vaccines have already been evaluated for their adverse events profiles and recommended by ACIP based on their safety records.Table 2: Outcomes and Rankings
Table 2: Outcomes and Rankings
Outcome
Importance*
Included in evidence profileIncidence of hepatitis B
Important
YesMorbidity related to hepatitis B
Important
YesMortality related to hepatitis B
Important
YesSerious adverse events associated with the 2-dose HepB vaccine*
Critical
YesTable 3a. Summary of studies reporting seroprotection (SPR)*
Table 3a. Summary of Studies Reporting Cardiovascular Events
Study
Population
n/N (%)
HBsAg-1018
(Heplisav-B)
n/N (%)
HBsAg-Eng
(Engerix-B)
Difference (95% CI)
Risk ratio (95% CI)
Study limitations (Risk of Bias)Hyer, 2018
HBV-10:
2,415 adults
18–55 years
0/1,810 (0%)
0/605 (0%)
—
Not seriousHBV-16:
2,449 adults
40–70 years
3/1,968 (0.2%)
2/481 (0.4%)
-0.3% (-0.8%, 0.3%)
0.37 (0.06, 2.19)
Not seriousHBV-23:
8,368 adults
18–70 years
28/5,587 (0.5%)
6/2,781 (0.2%)
0.3% (0.03%, 0.5%)
2.32 (0.96, 5.60)
Not seriousJanssen, 2013
516 adults
18–75 years with chronic kidney disease
10/254 (3.9%)
8/262 (3.1%)
0.9% (-2.3%, 4.1%)
1.29 (0.52, 3.21)
Not seriousBruxvoort, 2021
69,625 adults routinely vaccinated in a US health system
52/31,183 (0.2%)
71/38,442 (0.2%)
0.0% (-0.1%, 0.0%)
HR 0.92 (0.63, 1.39)
Not seriousTable 3b. Summary of Studies Reporting Serious Adverse Events
Table 3b. Summary of Studies Reporting Serious Adverse Events
Study
Population
n/N (%)
HBsAg-1018
(Heplisav-B)
n/N (%) HBsAg-Eng
(Engerix-B)
Difference (95% CI)
Risk ratio (95% CI)
Study limitations (Risk of Bias)Halperin, 2006
99 healthy adults
18–28 years
1/51 (2.0%)
4/48 (8.3%)
-6.4% (-15.1%, 4.4%)
0.24 (0.03, 2.03)
Not seriousSablan, 2012
412 healthy adults
40–70 years
10/206 (4.9%)
13/206 (6.3%)
-1.5% (-5.9%, 3.0%)
0.77 (0.35, 1.71)
Not seriousJanssen, 2013
516 adults
18–75 years with chronic kidney disease
68/254 (26.8%)
76/262 (29.0%)
-2.2% (-10.0%, 5.5%)
0.92 (0.70, 1.22)
Not seriousHyer, 2018
HBV-10:
2,415 adults
18–55 years
28/1,810 (1.5%)
13/605 (2.1%)
-0.6% (-1.9%, 0.7%)
0.72 (0.38, 1.38)
Not seriousHBV-16:
2,449 adults
40–70 years
76/1,968 (3.9%)
23/481 (4.8%)
-0.9% (-3.0%, 1.2%)
0.81 (0.51, 1.27)
Not seriousHBV-23:
8,368 adults
18–70 years
345/5,587 (6.2%)
148/2,781 (5.3%)
0.9% (-0.2%, 1.9%)
1.16 (0.96, 1.40)
Not seriousTable 4. Grade Summary of Findings Table
Table 4. Grade Summary of Findings Table
Certainty assessment
No of patients **HBsAg-1018**
No of patients C**HBsAg-Eng**
Effect Relative (95% CI)
Effect Absolute (95% CI)
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations**Cardiovascular events – RCTs**4
randomized trials
not serious
serious a
not serious
serious b
none
41/9619 (0.4%)
16/4129 (0.4%)
**RR 1.33**
(0.58 to 3.08)
**128 more per 100,000**
(from 163 fewer to 806 more)
Type 3, Low
CRITICAL**Cardiovascular events – observational**1
observational studies
not serious
not serious
not serious
serious b
none
52/31183 (0.2%)
71/38442 (0.2%)
**HR 0.92**
(0.63 to 1.32)
**15 fewer per 100,000**
(from 68 fewer to 59 more)
Type 4, Very Low
CRITICAL**Serious adverse events**6
randomized trials
not serious
not serious
not serious
not serious
none
528/9876 (5.3%)
277/4383 (6.3%)
**RR 0.96**
(0.79 to 1.16)
**253 fewer per 100,000**
(from 1,327 fewer to 1,011 more)
Type 1, High
CRITICAL
**CI:** Confidence interval; **RR:** Risk ratio; **HR:** Hazard Ratio
a. Heterogeneity of estimates across studies. I2 = 43%
b. Few events suggest fragility of the estimate. 95% CI cannot exclude the possibility of meaningful harm.Appendix 1: Evidence retrieval strategies used for systematic review*
Appendix 1: Evidence retrieval strategies used for systematic review
Database
Strategy
Run Date**Medline**
**(OVID)**
**1946-**
hepatitis b vaccines/ OR ((hepatitis B ADJ5 vaccin*) OR (HBV ADJ5 vaccin*) OR recombivax hb OR engerix-b).ti,ab.
AND
Exp Adults/ OR (adult* OR elder* OR senior*).ti,ab.
AND
Ae.fs OR ad.fs OR review.pt OR (dose* OR dosage* OR administration OR schedule* OR routine OR universal OR adverse OR efficacy OR effective* OR safe* OR strateg* OR risk* OR guideline* OR recommendation*).ti,ab.
Limit to 2006 – ; Abstract Available
12/4/2019, updated 9/20/2021**Embase**
**(OVID)**
**1947-**
hepatitis b vaccine/ OR recombinant hepatitis B vaccine/ OR ((hepatitis B ADJ5 vaccin*) OR (HBV ADJ5 vaccin*) OR recombivax hb OR engerix-b).ti,ab.
AND
Exp Adults/ OR (adult* OR elder* OR senior*).ti,ab.
AND
Ae.fs OR ad.fs OR do.fs. OR review.pt OR (dose* OR dosage* OR administration OR schedule* OR routine OR universal OR adverse OR efficacy OR effective* OR safe* OR strateg* OR risk* OR guideline* OR recommendation*).ti,ab.
Limit to 2006 – ; NOT pubmed/medline; Abstract Available
12/4/2019, updated 9/20/2021**CINAHL**
**(Ebsco)**
(MH “Hepatitis B Vaccines+”) OR ((“hepatitis B” N5 vaccin*) OR (HBV N5 vaccin*) OR “recombivax hb” OR “engerix-b”)
AND
(MH “Adult+”) OR (adult* OR elder* OR senior*)
AND
(dose* OR dosage* OR administration OR schedule* OR routine OR universal OR adverse OR efficacy OR effective* OR safe* OR strateg* OR risk* OR guideline* OR recommendation* OR review*)
Limit to 2006 – ; exclude Medline records; Abstract Available
12/4/2019, updated 9/20/2021**Cochrane Library**
[mh “Hepatitis B Vaccines”] OR ((“hepatitis B” N5 vaccin*) OR (HBV N5 vaccin*) OR “recombivax hb” OR “engerix-b”):ti,ab
AND
(dose* OR dosage* OR administration OR schedule* OR routine OR universal OR adverse OR efficacy OR effective* OR safe* OR strateg* OR risk* OR guideline* OR recommendation* OR review*):ti,ab
Limit to 2006- ; Abstract Available
12/4/2019, updated 9/20/2021*Exclusion criteria: articles dated earlier than year 2006, articles discussing vaccines not licensed in United States, articles not addressing the population of interest, and articles where data could not be abstractedTop of Page
							
					
							Last Reviewed:  March 30, 2022						Source: 	National Center for Immunization and Respiratory Diseases
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